Abstract
BackgroundFucoidan extract (FE), an enzymatically digested compound with a low molecular weight, is extracted from brown seaweed. As a natural compound with various actions, FE is attractive, especially in Asian countries, for improving the therapeutic efficacy and safety of cancer treatment. The present study was carried out to investigate the anti-tumor properties of FE in human carcinoma cells and further examine the underlying mechanisms of its activities.Methodology/Principal FindingFE inhibits the growth of MCF-7, MDA-MB-231, HeLa, and HT1080 cells. FE-mediated apoptosis in MCF-7 cancer cells is accompanied by DNA fragmentation, nuclear condensation, and phosphatidylserine exposure. FE induces mitochondrial membrane permeabilization (MMP) through loss of mitochondrial membrane potential (ΔΨm) and regulation of the expression of Bcl-2 family members. Release of apoptosis-inducing factor (AIF) and cytochrome c precedes MMP. AIF release causes DNA fragmentation, the final stage of apoptosis, via a caspase-independent mitochondrial pathway. Additionally, FE was found to induce phosphorylation of c-Jun N-terminal kinase (JNK), p38, and extracellular signal-regulated kinase (ERK) 1/2, and apoptosis was found to be attenuated by inhibition of JNK. Furthermore, FE-mediated apoptosis was found to involve the generation of reactive oxygen species (ROS), which are responsible for the decrease of ΔΨm and phosphorylation of JNK, p38, and ERK1/2 kinases.Conclusions/SignificanceThese data suggest that FE activates a caspase-independent apoptotic pathway in MCF-7 cancer cells through activation of ROS-mediated MAP kinases and regulation of the Bcl-2 family protein-mediated mitochondrial pathway. They also provide evidence that FE deserves further investigation as a natural anticancer and cancer preventive agent.
Highlights
The polysaccharide known as fucoidan is extracted from marine brown algae and is known to contain large proportions of L-fucose and sulfate, along with low amounts of xylose, uronic acid, and galactose [1,2]
The phosphorylation of Jun N-terminal kinase (JNK), p38, and ERK1/2 was detectable after as little as 30 minutes of Fucoidan extract (FE) treatment and persisted for at least 6 h of treatment. These results indicate that the JNK, p38, and ERK1/2 pathways were activated in response to FE in MCF-7 cancer cells
Fucoidan is a potent inducer of apoptosis in various cancer cell lines
Summary
The polysaccharide known as fucoidan is extracted from marine brown algae and is known to contain large proportions of L-fucose and sulfate, along with low amounts of xylose, uronic acid, and galactose [1,2]. Several mechanisms have been postulated to underlie the anticancer activity of fucoidan, including induction of apoptosis in cells derived from human lymphoma, promyelocytic leukemia, colon carcinoma, breast carcinoma, and hepatoma and prevention of angiogenesis and invasion in HT1080 fibrosarcoma cells [9,10,11,12,13,14,15]. The molecular mechanisms involved in the anticancer action of fucoidan are complex, and the targets and molecular mechanisms by which it initiates death of cancer cells are incompletely understood. The present study was carried out to investigate the anti-tumor properties of FE in human carcinoma cells and further examine the underlying mechanisms of its activities
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